Aurora B kinase regulates the postmitotic endoreduplication checkpoint via phosphorylation of the retinoblastoma protein at serine 780 Journal Article
| Authors: | Nair, J. S.; Ho, A. L.; Tse, A. N.; Coward, J.; Cheema, H.; Ambrosini, G.; Keen, N.; Schwartz, G. K. |
| Article Title: | Aurora B kinase regulates the postmitotic endoreduplication checkpoint via phosphorylation of the retinoblastoma protein at serine 780 |
| Abstract: | The phenotypic change characteristic of Aurora B inhibition is the induction of polyploidy. Utilizing specific siRNA duplexes and a selective small molecule inhibitor (AZD1152) to inhibit Aurora B activity in tumor cells, we sought to elucidate the mechanism by which Aurora B inhibition results in polyploidy. Cells treated with AZD1152 progressed through mitosis with misaligned chromosomes and exited without cytokinesis and subsequently underwent endoredu-plication of DNA despite activation of a p53-dependent pseudo G1 checkpoint. Concomitant with polyploid cell formation, we observed the appearance of Rb hypophosphorylation, an event that occurred independently of cyclin-dependent kinase inhibition. We went on to discover that Aurora B directly phosphorylates Rb at serine 780 both in vitro and in vivo. This novel interaction plays a critical role in regulating the postmitotic checkpoint to prevent endoredupli-cation after an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein. © 2009 by The American Society for Cell Biology. |
| Keywords: | controlled study; protein phosphorylation; human cell; flow cytometry; mitosis; phenotype; enzyme inhibition; protein protein interaction; small interfering rna; protein binding; hct116 cells; cell fate; enzyme activity; phosphorylation; protein p53; protein kinase inhibitors; regulatory mechanism; amino acid sequence; molecular sequence data; protein-serine-threonine kinases; tumor cell; tumor suppressor protein p53; tumor suppressor protein; quinazolines; retinoblastoma protein; histones; polyploidy; phosphoserine; 2 [[3 [4 [5 [2 (3 fluoroanilino) 2 oxoethyl] 1h pyrazol 3 ylamino] 7 quinazolinyloxy]propyl](ethyl)amino]ethyl dihydrogen phosphate; phosphoric acid esters; aurora b kinase; cytokinesis; endoreduplication |
| Journal Title: | Molecular Biology of the Cell |
| Volume: | 20 |
| Issue: | 8 |
| ISSN: | 1059-1524 |
| Publisher: | The American Society for Cell Biology |
| Date Published: | 2009-04-15 |
| Start Page: | 2218 |
| End Page: | 2228 |
| Language: | English |
| DOI: | 10.1091/mbc.E08-08-0885 |
| PUBMED: | 19225156 |
| PROVIDER: | scopus |
| PMCID: | PMC2669029 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: MBCEE" - "Source: Scopus" |
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